“Connective tissue” is defined as tissue of mesodermal origin, for example collagen fibroblasts and fatty cells. Connective tissue supports organs, fills the spaces between organs, and forms tendons and ligaments. As used herein, the term “connective tissue” generally refers to any type of biological tissue with an extensive extracellular matrix.
“Connective tissue diseases” are a collection of disorders and ailments, which comprise connective tissue. Connective tissue diseases can result from, as well as give rise to, a variety of neuropathies. Such neuropathies include diabetic and non-diabetic neuropathies, including complex regional pain syndrome, femoral nerve palsy, and Guillain-Barre syndrome. Connective tissue diseases may be segregated into more discrete pathologies arising from chronic disorders such as degenerative ligament disease, or acute manifestations such as ruptured tendons and ligaments resulting from trauma. These disorders have many pathologic events in common and all result in pain, inflammation, and instability of the affected joint. In many cases, connective tissue diseases can lead to progressive degeneration of the joint or associated organ with increasing discomfort and difficulty of use. Moreover, peripheral neuropathies commonly associated with diabetes frequently manifest themselves as joint disease, poor tissue healing, and/or a compromised immune response.
While the etiology of the various diseases that manifest themselves as connective tissue disease are complex, similar patho-physiologic responses may play a major role in the progression of connective tissue disease and ligament degeneration. One disease with major complications resulting in tissue and joint damage is diabetes. Diabetic pathologies include defects in connective tissue, such as poor wound healing and diminished bone formation and growth. In these tissues, the major protein component is collagen and studies have shown that, in diabetic rats, collagen production was significantly reduced in after induction of diabetes (Spanheimer, 1988).
While the causes of various diabetic neuropathies are not completely clear, it is thought that increased blood glucose levels over time result in damage to the blood vessels, connective tissue, nerves and other organs. Further, it is unclear whether a single diabetic pathology promotes the pathological condition of another tissue, or whether each separate pathological condition independently results from increased blood glucose levels. In short, a variety of disorders are associated with diabetes, and the presentation of each particular disorder often differs widely from individual to individual. Because the organs and tissues affected are can be quite different from patient to patient, treating diabetic complications is a highly individualized undertaking.
Peripheral nerve disorders are prevalent and can be debilitating, especially among diabetic populations. This is particularly evident in the connective tissues of joints, including tendons, ligaments and cartilage, due to their constant use and visible loss of function. In general, damaged nerves have limited potential for regeneration, and healing in joints following nerve damage is slow and often results in permanent joint damage. At present, many joint disorders are managed through surgical or drug treatments that inhibit painful stimuli from the damaged joint. Despite the prevalence of nerve disorders, little work has been done to elucidate how damage to nervous tissue leads to structural damage to various connective tissues.
Conventional treatments to manage pain resulting from peripheral neuropathies include surgical intervention, chemical intervention and analgesics. Conventional treatments include ligating or transecting the sympathetic nerves to the brachial or femoral plexus. Conventional treatment also includes chemical sympathectomy: chemically blocking sympathetic nerve transduction using guanethidine. In addition, drugs such as capsaicin can be used to block sensory stimuli both topically and internally. In severe instances of femoral pain, femoral nerve transection is an option of last resort.
Recently it has been discovered that classical modes of neuronal stimulation via neuro-transmitters such as epinephrine, nor-epinephrine and acetylcholine are supplemented by the action of other neurogenic compounds. These neurogenic compounds include neuroactive peptides and peptide neurotransmitters. Many of these compounds were originally isolated from the gut and thought to modulate digestion. However, continuing research suggests that these neurogenic compounds are produced throughout the nervous system and have complex effects.
Among the more well known neuroactive peptides (NPs) are somatostatin, calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP), Substance P (SP), enkephalin, neuropeptide Y (NPY), neurotensin, thyrotropin-releasing hormone (TRH), cholecystokinin (CCK), galanin and dynorphin, to name a few. (See, generally, “The Biochemical Basis of Neuropharmacology,” Cooper, Bloom and Roth, 8th ed., Oxford University Press, New York, 2003, pp. 321-356 and the references cited therein).
Ligaments are a class of connective tissue that are composed primarily of collagen and are located in joints where their primary role is to connect bones to other bones, thereby maintaining the integrity of the joint. Ligament injuries occur frequently in all age groups at all activity levels and may result from acute trauma or underlying disease states.
Healing potential varies widely among ligaments. The anterior cruciate ligament (ACL) has very little healing potential, while the medial cruciate ligament (MCL) has a greater healing potential (although certainly not ideal). Even in ligaments that heal reasonably well (e.g., the MCL), mechanical, biochemical, and morphological alterations continue to persist at least two years post-injury. See, for example, Frank et al. (1995) J. Ortho. Res. 13:157-165. The scar tissue associated with ligament healing is mechanically inferior and compositionally abnormal as compared to uninjured tissue. Healing after ligament injury can then result in ligament laxity, joint instability, prolonged pain, and abnormal joint motion. In Achilles tendon, Ackermann et al. (Ackermann et al., 2002) suggest that nerve regeneration is a prerequisite for healing based in part upon the abundance of neuropeptide Y (NPY) and calcitonin gene-related peptide (CGRP) in the healing tissue. More recently, the Ackerman et al. group discovered that levels of substance P (SP) and CGRP change over the course of tendon healing and remodeling (Ackermann et al., 2003).
Compelling indirect evidence supports the concept that peripheral nerves and peripheral neuropeptides are essential to maintain joint tissues. For example, patients who suffer spinal cord injury, head trauma, or severe burns that damage nerves are more susceptible to heterotopic bone formation or ankylosis of proximal joints. The detailed molecular mechanisms behind this abnormal bone formation are unknown. Proper functioning of the peripheral nervous system, however, appears essential to maintaining healthy joint tissues.
At the cellular level, healing involves cell detachment and re-attachment around the injury site, cell migration, and cell proliferation. Cell migration and proliferation are crucial for healing, and there is mounting evidence that local neuropeptides from the peripheral nervous system (PNS) play an essential role in orchestrating these inflammatory responses (Schaffer et al., 1998).
Peripheral neuropathy is a class of disorders in which tissue damage results from destruction of or damage to peripheral nerves. Peripheral neuropathy includes nerve injury, compression, ischemia, and disease (Association, 2000; Promotion, 2000). Symptoms of peripheral neuropathy vary depending on the types of nerves that are damaged. Damage to sensory nerves can result in dysesthesia (perception of abnormal sensations), while damage to sympathetic nerves can result in wide spread organ problems due to alterations in blood flow (Association, 2000).
One prevalent form of peripheral neuropathy results as a complication of diabetes. Diabetic neuropathy affects approximately 60-70% of diabetics and can degenerate into Charcot joints, which are characterized by joint effusion, fractures, ligament laxity, subluxation, and/or joint dislocation (Association, 2000). Another peripheral neuropathy is femoral mononeuropathy, which results from injury, compression, or surgical transection of the femoral nerve. Femoral mononeuropathy leads to knee “buckling”, ligament laxity, decreased patellar reflexes, and medial leg numbness (Sekul, 2001). Other conditions that lead to neuropathy include Complex Regional Pain Syndrome/Reflex Sympathetic Dystrophy Syndrome (CRPS/RSDS), Charcot-Marie-Tooth disease, Guillain-Barre syndrome, rheumatoid arthritis, and neuropathy secondary to ischemia or specific drugs (Stroke, 2001 a, b; Stroke, 2001c; Stroke, 2001d). Neuromediators, including the neuropeptides SP, CGRP, and NPY, play a pivotal role in the genesis of pain associated with CRPS/RSDS, and may have a key role in the degeneration of joint tissues in patients who experience CRPS/RSDS.
Release of neuropeptides following injury is generally associated with pain at the site of injury. Thus, chemical inhibitors of sensory and sympathetic nerves are conventionally used to provide pain management in cases of tendonitis, osteoarthritis, and rheumatoid arthritis. As noted earlier, surgical techniques are also used to inhibit nerves to manage pain and hyperhydrosis in extreme cases.
Chemical inhibition of sympathetic nerves can be accomplished with guanethidine, an anti-hypertensive agent that acts in postganglionic sympathetic nerve endings by blocking the release of norepinephrine from nerve terminals (Kirschenbaum and Rosenberg, 1984). Guanethidine has been used as an anti-hypertensive drug for more than 40 years due to the fact that it blocks the sympathetic PNS in two ways: 1) it causes a release of norepinephrine from nerve endings; and 2) it blocks the normal release of catecholamines resulting from nerve stimulation. Guanethidine is conventionally used in the treatment of certain joint disorders, including reflex sympathetic dystrophy (Sudeck's atrophy) (Field and Atkins, 1993), neuralgia of the hands (Wahren et al., 1995), and shoulder pain caused by rheumatoid arthritis, rotator cufftendonitis, and osteoarthritis (Gado and Emery, 1996).
Analogously, chemical inhibition of sensory nerves can be achieved through administration of capsaicin, an analgesic that causes the release of SP from afferent nerve fibers. Capsaicin is one of the main constituents of hot, red chili peppers. Capsaicin inhibits type C cutaneous sensory fibers (Dray, 1992) and administration of capsaicin releases substance P (Jessell et al., 1978) from these fibers. Substance P depletion by capsaicin has been shown to be detrimental to wound healing (Dunnick et al., 1996; Dwyer et al., 2003). A decrease in immune cells (CD4+ and CD8+ cells) in whole blood has been shown to result from administering capsaicin (Santoni et al., 1996) to rats, which may account for poor healing of tissues following administration of capsaicin. Capsaicin, like guanethidine, has been conventionally used to treat joint disorders, including: neuralgia (Carter, 1991), surgical neuropathic pain, rheumatoid arthritis, osteoarthritis, and temporomandibular joint pain (Surh and Lee, 1996).
While techniques of inhibiting sensory information resulting from peripheral neuropathies affords relief from pain, these techniques do not treat the underlying cause of the pain, and in many instances may further potentiate the connective tissue degeneration that is the source of, or results from, pain induction.